Project Summary Changes in the microvasculature of the brain with age have been observed in post-mortem studies using histology. These changes include decreases in length density, increased tortuosity, reductions in blood flow, and formation of string vessels. The severity of these changes has been observed to be greater with neurodegenerative disorders such as Alzheimer's disease. Currently, there is no established way to measure the state of the capillaries and microvessels in the brain without using invasive or destructive histology. We propose to use diffusion weighted Magnetic Resonance Imaging (MRI) to derive quantitative biomarkers to measure the state of the microvasculature in the brain. By creating noninvasive biomarkers to quantify the state of the biomarkers on a voxel-by-voxel basis, changes over time can be measured. This project will develop the imaging and estimation technology to quantify these biomarkers, and perform important validation steps to demonstrate proof of concept on a population of health young and aged subjects. Subsequently, the biomarkers will be applied to a small cohort of subjects with Alzheimer's disease. By developing novel, neuroimaging based biomarkers to quantify the state of the microvasculature, longitudinal studies examining the process of microvascular changes in the brain will be made possible.